Abstract Human brain is still one of the mysteries in science and many brain disease and disorders such as Alzheimer's disease have left a huge burden on individuals, their family, and the society. Neurodegenerative disease is characterized by a progressive loss of neurons that lead to dementia. The most prevalent form of dementia in elderly is Alzheimer disease (AD). The number of people with AD is expected to reach 14 million by year 2050. While there are thousands of PET scanners in the States today, there are not designed or optimized for brain imaging. These PET scanners are whole-body systems that typically have detector spatial resolution of 4-6 mm FWHM; however this resolution is not sufficient to image brain with fine structures that is required to study the Alzheimer's disease or other neurological disorders. There are only few PET systems dedicated to brain imaging that are commercially available or in the process of FDA approval. However, none of them provides better than 2mm FHWM spatial resolution and all have less than optimal absorption efficiency for the 511 keV gamma rays. The main objective of this project is to develop a novel high-resolution and high- sensitivity PET system dedicated to brain imaging. The main innovation is a novel detector concept which is flexible with depth of interaction capability and single-side readout that can provide high transverse resolution as well. We will first simulate the envisaged PET system and compare its expected performance when using GFAG crystals compared to the mainstream LYSO scintillators. We will follow by optimizing both the transverse and DOI position decoding of GFAG scintillators to achieve intrinsic detector resolution of 1.2 mm FWHM and at least 4 levels of DOIs with single-side SiPM readout. We plan to build a prototype system using two fully characterized detector modules and perform basic phantom imaging. Owing to the compact, cost- effective, and mobile design of our proposed PET scanner together with its superior performance, we believe successful development of the system will likely have a transformational impact on our understanding of brain and neurodegenerative diseases including the AD.